Cholesterol regulates the rate of sterol synthesis by controlling the level of microsomal 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase. The longterm goal of these investigations is to elucidate the molecular and biochemical mechanisms governing the level and activity of HMG-CoA reductase. The approach will be to determine the site at which exogenous cholesterol acts to suppress the synthesis of HMG-CoA reductase and thereby decrease the rate of cholesterol synthesis. Rates of MHG-CoA reductase synthesis and degradation will be determined immunochemically in cell cultures of animal and human origin. Individuals with defective cholesterol regulation of HMG-CoA reductase and cholesterol synthesis exhibit serum hypercholesterolemia and atheroschlerosis. These individuals are the source of established cell culture lines which will be used to help elucidate the site and mechanism of cholesterol regulation of HMG-CoA reductase synthesis. BIBLIOGRAPHIC REFERENCES: Schimke, R.T., McKnight, G.S. and Shapiro, D.J. (1975) in G Litwack (Ed.) Biochemical Actions of Hormones, Academic Press, New York, Vol. III, p. 246-271. Shapiro, D.J., (1976) Messenger RNA Stability and Control of Gene Expression, BioScience.